Phosphonoalkylquinolin-2-ones as novel antagonists of non-NMDA ionotropic excitatory amino acid receptors

ABSTRACT

The present invention pertains to antagonists of excitatory amino acid receptors, their method of preparation as well as compositions pertaining to them, which have the general formula: ##STR1## wherein n is 0, 1, 2, or 3; R 1  and R 2  are selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C 1  to C 6  lower alkyl and C 7  to C 12  higher alkyl, aryl and aralkyl; and the pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention pertains to novel non-N-methyl-D-aspartateexcitatory amino acid (EAA) receptor antagonists and particularly tonovel, potent and selective antagonists of kainic acid (KA) and AMPA[(R,S)-α-aminomethyl-3-hydroxy-5-methylisoxazole propionic acid]-typereceptors having anxiolytic, anticonvulsant, antiepileptic, analgesic,antiemetic, neuroprotective and cognition enhancing actions achievedthrough the antagonism of these receptors. In particular, the inventionis directed to: substituted 4-phosphonoalkylquinolin-2-ones and theirinteraction with KA and AMPA receptors, their pharmaceuticallyacceptable salts, and to uses thereof.

2. Description Of the Prior Art

Excitatory amino acids (EAAs) mediate a substantial portion of theneurochemical synaptic activity occurring in the central nervous system.Current understanding recognizes at least three major ionotropicreceptors for EAAs. Most commonly identified by prototypical agonists,these include:

(1) receptors activated by AMPA[(R,S)-α-aminomethyl-3-hydroxy-methylisoxazole propionic acid], a cyclicanalog of L-glutamate (GLU), (2) receptors recognizing the pyrrolidineneurotoxin kainic acid (KA), and three receptors responding toN-methyl-D-aspartate (NMDA), a synthetic analog of L-aspartate [D. R.Curtis, A. W. Duggar, D. Felix, G. A. R. Johnston, A. K. Tebecis and J.C. Watkins, Brain Res., 41, 283-301 (1972); J. C. Watkins and R. H.Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165-204 (1981); A. C. Fosterand G. Fagg, Brain Res. Rev., 7, 103-164 (1984)]. In addition to thesemajor ion channel-linked receptors, evidence now suggests the presenceof metabotropic EAA receptors which directly activate second messengersystems [D. Schoepp, J. Brockaert and F. Soladeczek, In C. Lodge and G.L. Collinridge (eds.) Tr. Pharmacol. Sci., Special Report, "ThePharmacology of Excitatory Amino Acids," Elsevier, Cambridge, U.K.,74-81 (1991)]. Furthermore, it is now apparent that the NMDA-mediatedionotropic responses are subject to complex regulatory influences and,that this particular recognition site may exist as a supramolecularentity similar to the GABA/benzodiazepine/barbituate effector proteins[E. Costa, Neuropsycholpharmacology, 2, 167-174 (1989)].

In general EAA agonists are potent convulsants in animal models.Additionally, AMPA, KA and the endogenous NMDA agonist, quinoline acid(QUIN) and the mixed ionotropic/metabotropic agonist ibotenic acid havebeen used to produce laboratory models of neurodegenerative disorders[K. Biziere, J. T. Slevin, R. Zaczek, J. S. Collins and J. T. Coyle. InH. Yoshida, Y. Hagihara and S. Ebashi (eds.), "Advances in Pharmacologyand Therapeutics," New York: Pergamon 271-276 (1982); R. Schwarcz, E. O.Whetsell and R. M. Mango, Science, 219, 316-318 (1983)]. It has beensuggested for some time that a dysfunction in EAA neurotransmission maycontribute to the neuropathology associated with the epilepsies andneurodegenerative conditions [B. Meldrum and M. Williams (eds.),"Current and Future Trends in Anticonvulsant, Anxiety and StrokeTherapy," Liss, New York: Wiley (1990)],

The development of selective NMDA antagonists has further expanded theunderstanding of EAA neurotransmission, physiology and pathophysiologyin the mammalian brain. In particular, substantial preclinical evidenceis now available suggesting the NMDA receptor antagonists may be usefulas anxiolytics, anticonvulsants, antiemetics, antipsychotics or musclerelaxants, and that these compounds may prevent or reduce neuronaldamage in instances of cerebral ischemia, hypoxia, hypoglycemia ortrauma [R. P. Simon, J. H. Swan, T. Griffiths and B. S. Meldru, Science,226, 850-852 (1984); D. N. Stephens, B. S. Meldrum, R. Weidman, C.Schneider and M. Grutzner, Psychopharmacology, 90, 166-169 (1986); D.Lodge and G. L. Collinridge (eds.) "The Pharmacology of Excitatory AminoAcids," Elsevier Trends Journals, Cambridge, U.K. (1991); A. I. Fader,J. A. Ellison and L. J. Noble, Eur. J. Pharmacol., 175, 165-174 (1990)].

Given the broad therapeutic potential of EAA antagonists, it is notsurprising that efforts have been initiated to identify antagonistcompounds. The advent of potent and selective antagonists of EAAsexemplified by α-amino-ω-phosphonoalkylcarboxylic acids has beenprovided a point of departure for the pharmacologic intervention of EAAaction at their receptors [J. C. Watkins, Can. J. Physiology Pharmacol.,69, 1064-1075 (1991)]. While there has been substantial success infinding competitive and non-competitive antagonists of non-NMDAreceptors, there are few reports of potent and selective antagonists ofKA or AMPA-type EAA receptors [J. C. Watkins, P. Krogsgaard-Larsen andT. Honore, In D. Lodge and G. L. Collinridge (eds.), "The Pharmacologyof Excitatory Amino Acids," Elsevier Trends Journals, Cambridge, U.K.,4-12 (1991); M. J. Sheardown, E. O. Nielson, A. J. Hansen, P. Jacobsenand T. Honore, Science, 247, 571-573 (1990); A. Frasden, J. Drejer andA. Shousboe, J. Neurochem., 53, 297-300 (1989)]. Identification of suchantagonists is important since these agents are expected to share manyof the potential therapeutic actions of antagonists of NMDA-type EAAreceptors.

Other related compounds having NMDA antagonist activity have beenreported in Rzeszotarski et al., U.S. Pat. No. 4,657,899. In particular,Rzeszotarski et al. disclose potent and selective EAA neurotransmitterreceptor antagonists having the general formula: ##STR2## wherein R₁ andR₂ are the same or different and are selected from the group consistingof hydrogen, lower alkyl, halogen, amino, nitro, trifluoromethyl orcyano, or taken together are --CH═CH--CH═CH--; n and m=0, 1, 2, or 3;and the pharmaceutically acceptable salts and the2-acetamido-2-carboethoxy esters thereof. Rzeszotarski et al. alsodisclose specific compounds, including 2-amino-3-[2-(2-phosphonoethyl)phenyl]propanoic acid, 2-amino-3-[2-(3-phosphonopropyl) phenyl]pentanoicacid, 2-amino-5-[2-phosphonomethylphenyl]pentanoic acid, and2-amino-3-[2-phosphonomethylphenyl]propanoic acid which are disclosed asantagonists of NMDA and show very low binding affinity for kainatereceptors; see Table I on column 13. The valuable pharmacologicalproperties of the present new compounds are particularly surprising inview of the compounds disclosed and described in U.S. Pat. No.4,657,899.

SUMMARY OF THE INVENTION

The present invention provides an excitatory amino acid KA/AMPA acidreceptor antagonist compound having the general formula: ##STR3##wherein n is 0, 1, 2 or 3; R1 and R2 are selected from the groupconsisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy,hydroxyl, hydroxymethyl, C1 to C6 lower alkyl and C7 to C12 higheralkyl, aryl, and aralkyl; and the pharmaceutically acceptable saltsthereof.

More particularly, the invention provides a potent and selectiveexcitatory amino acid receptor antagonist having the general formula:##STR4## wherein R1 and R2 are selected from the group consisting ofhydrogen, halogen, nitro, and C1 to C6 lower alkyl.

Another aspect of the invention involves use of the pharmaceuticalcompositions for relieving pain, treatment of convulsions or epilepsy,enhancing cognition, treating psychosis, preventing neurodegeneration,treating cerebral ischemia or trauma-induced damage, and treatingemesis.

A further aspect of this invention involves a method for antagonizingexcitatory amino acid KA and/or AMPA receptors by utilizing a compoundhaving the general formula: ##STR5## wherein n is 0, 1, 2 or 3; R1 andR2 are selected from the group consisting of hydrogen, halogen,halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C1 to C6lower alkyl and C7 to C12 higher alkyl, aryl and aralkyl; and thepharmaceutically acceptable salts thereof.

The compounds of the present invention describe a novel class of EAAantagonists in which the phosphonoalkyl moiety has been appended to aheterocyclic ring; specifically, to the 4-position of a substitutedquinolin-2-one. These compounds have been found to potently andselectively antagonize KA/AMPA neurotransmission, and represent a novelclass of such antagonists.

Particularly preferred specific compounds include:

7-Chloro-4-phosphonoethylquinolin-2-one

7-Chloro-4-phosphonomethylquinolin-2-one

7-Iodo-4-phosphonomethylquinolin-2-one

5,7-Dichloro-4-phosphonomethylquinolin-2-one

6,7-Dichloro-4-phosphonomethylquinolin-2-one

DETAILED DESCRIPTION OF THE INVENTION

The structure and formulation of the novel compounds of the inventionwas the result of an extensive research effort into the antagonism ofexcitatory amino acid (EAA) neurotransmission with focus on the kainicacid (KA) and AMPA subtypes of EAA receptor.

It is generally accepted that L-glutamic acid (GLU) is the principalexcitatory neurotransmitter in the vertebrate central nervous system(CNS). Ion channel-linked or "ionotropic" EAA receptor subtypes includethose selectively activated by N-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainicacid (KA). A "metabotropic" GLU receptor coupled to phospholipidmetabolism and a putative GLU autoreceptor have also been identified.L-glutamic acid is also believed to have an important physiological rolein the functioning of the CNS since a great majority of CNS neuronsutilize GLU as their neurotransmitter.

Beyond its involvement in excitatory neurotransmission, GLU has beensuggested to play a role in CNS pathologies characterized by heightenedneuronal activity or sensitivity, including epilepsy, ischemic ortrauma-induced neuronal damage, and certain neurologic andneurodegenerative disorders. Accordingly, the pharmacologicalmanipulation of GLU receptors may be therapeutically useful in thetreatment of several CNS disorders and diseases.

The NMDA receptor is the most well-characterized of the GLU receptorsubtypes because of the availability of potent and selectiveantagonists. D-(-)-2-amino-5-phosphonopentanoic acid (AP5) andD-(-)-2-amino-7-phosphonoheptanoic acid (AP7) were among the first NMDAantagonists identified and act competitively by binding to the GLUrecognition site.

Competitive NMDA antagonists have been demonstrated to be effective asanticonvulsant and cerebroprotective agents. A growing body of evidencealso suggests that blockade of non-NMDA receptors is useful in thetreatment of CNS disorders involving glutamatergic neurotransmission.This latter use has been supported by experiments in which KA-inducedseizures have been used as animal models of temporal lobe epilepsy inhumans. Another potential therapeutic use for a KA and/or AMPAantagonist in the treatment of neurodegenerative disorders is indicatedby the finding that intrastriatal administration of KA produces apattern of neuronal damage in rats similar to that observed inHuntington's chorea. Non-NMDA receptors have also been implicated inneurologic disorders including Lathyrism, an upper motor neuron diseasecharacterized by spastic paraparesis, and Guam's disease, a form ofamyotrophic lateral sclerosis.

In contrast to NMDA receptor antagonists a limited number of KA/AMPAreceptor antagonists have been described, the majority of which are weakand relatively non-selective; for this reason, the full characterizationof the functional and physiological properties of these receptors hasnot been realized to date. However, a series of quinoxalidiones wererecently identified as potent non-NMDA antagonists. The therapeuticpotential of these compounds is illustrated by their ability to protectagainst EAA agonist-induced cytotoxicity in cultured cortical neuronsand clonic seizures in neonatal rats.

The compounds of the present invention have been identified whichantagonize KA and AMPA-induced currents in Xenopus oocytes infected withrat brain mRNA. The structure and formulation of the novel compounds ofthis invention relate specifically to EAA receptors activated by eitherKA or AMPA for which only a limited number of quinoxalines have beenidentified as specific antagonists. See Watkins et al. In D. Lodge andG. L. Collinridge (eds.), "The Pharmacology of Excitatory Amino Acids,"Elsevier Trends Journals, Cambridge U.K., 4-12 (1991).

In a preferred embodiment, the novel compounds of the present inventionprovide potent antagonists having greater affinity for KA and AMPAreceptors and lesser or no affinity for other CNS receptors, renderingthe compounds very selective; this would permit one to selectivelyantagonize one EAA receptor in tissues also containing other EAAreceptors. Fewer side effects can be expected as a result of the greateraffinity and selectivity of the compounds of the present invention.

The present invention provides an excitatory amino acid KA/AMPA acidreceptor antagonist compound having the general formula: ##STR6##wherein n is 0, 1, 2, or 3; R1 and R2 are selected from the groupconsisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy,hydroxyl, hydroxymethyl, C1 to C6 lower alkyl and C7 to C12 higheralkyl, aryl and aralkyl; and the pharmaceutically acceptable saltsthereof.

More particularly, the invention provides a potent and selectiveexcitatory amino acid receptor antagonist having the general formula:##STR7## wherein R1 and R2 are selected from the group consisting ofhydrogen, halogen, nitro, and C1 to C6 lower alkyl; and thepharmaceutically acceptable salts thereof.

In a preferred aspect of the invention R1 and R2 are not both hydrogen,that is, when one is hydrogen the other is selected from a materialother than hydrogen.

Another aspect of the invention involves use of the pharmaceuticalcompositions for relieving pain, treatment of convulsions or epilepsy,enhancing cognition, treating psychosis, preventing neurodegeneration,treating cerebral ischemia or trauma-induced damage, and treatingemesis.

A further aspect of this invention involves a method for antagonizingexcitatory amino acid KA and/or AMPA receptors by utilizing a compoundhaving the general formula: ##STR8## wherein n is 0, 1, 2 or 3; R1 andR2 are selected from the group consisting of hydrogen, halogen,halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C1 to C6lower alkyl and C7 to C12 higher alkyl, aryl and aralkyl; and thepharmaceutically acceptable salts thereof.

Particularly preferred specific compounds include:

7-Chloro-4-phosphonomethylquinolin-2-one

7-Iodo-4-phosphonomethylquinolin-2-one

5,7 Dichloro-4-phosphonomethylquinolin-2-one

6,7 Dichloro-4-phosphonomethylquinolin-2-one

As used in the specification and claims, "alkyl" is a paraffinichydrocarbon group which may be derived from an alkane by dropping onehydrogen from the formula, such as methyl, ethyl, propyl, isopropyl,butyl, and so forth.

"Halogen" includes bromo, fluoro, chloro and iodo; "halomethyl" includesmono-, di-, and tri-halo groups inclduing trifluoromethyl; aminocompounds include amine (NH₂) as well as substituted amino groupscomprising alkyls of one through six carbons; "aryl" is an aromatic ringcompounds such as benzene, phenyl, naphthyl and substituted formsthereof; "aralkyl" is an aryl being attached through an alkyl chain,straight or branched, of from one through six carbons, such as aphenylpropyl group.

Abbreviations used in this specification have the following meanings:MCPBA is 3-chloroperoxybenzoic acid (ClC₆ H₄ CO₃ H), THF istetrahydrofuran, MsCl is methanesulfonyl chloride (CH₃ SO₂ Cl), TBAH istetrabutylammonium hydrogen sulfate ([CH₃ (CH₂)₃ ]NHSO₄), NBS isN-bromosuccinimide, TMS is trimethylsilyl (Si(CH₃)), GLU is glutamate,CNQX is 6-cyano-7-nitroquionoxaline-2,3-dione, nd means not determined,and TLC is thin layer chromatography.

The preparation of pharmaceutically acceptable salts of compounds of thepresent invention may be accomplished by a variety of methods known tothose skilled in the art of synthetic organic chemistry. Appropriatepharmaceutically acceptable salts within the scope of the invention arethose derived from mineral acids such as hydrochloric acid, phosphoricacid, nitric acid and sulfuric acid; and organic acids such as tartaricacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, and the like, giving the hydrochloride, sulfate, phosphate,nitrate, methanesulfonate, tartrate, benzenesulfonate,p-toluenesulfonate, and the like, respectively or those derived frombases such as suitable organic and inorganic bases. Examples of suitableinorganic bases for the formation of salts of compounds of thisinvention include the hydroxides, carbontates, and bicarbonates ofammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc,and the like.

Salts may also be formed with suitable organic bases. Bases suitable forthe formation of pharmaceutically acceptable base addition salts withcompounds of the present invention include organic bases which arenon-toxic and strong enough to form such salts. These organic bases forma class whose limits are readily understood by those skilled in the art.Merely for purposes of illustration, the class may be said to includemono-, di-, and trialkylamines, such as methylamine, dimethylamine, andtriethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-,and triethanolamine; amino acids such as arginine, and lysine;guanidine; N-methyl-glucosamine; N-methylglucamine; L-glutamine;N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine;tris(hydroxymethyl) aminomethane; and the like. (See for example,"Pharmaceutical Salts," J. Pharm. Sci., 66 (1): 1-19 (1977).

The preparation of the compounds for administration in pharmaceuticalpreparations may be accomplished in a variety of ways well known tothose skilled in the art of pharmacy. In parenteral administration ofthe novel compounds and compositions of the invention the compounds maybe formulated in aqueous infection solutions which may containantioxidants, buffers, bacteriostats, and other conventionalpharmaceutical excipients. Extemporaneous injection solutions may beprepared from sterile pills, granules or tablets which may containdiluents, dispersing and surface active agents, binders, and lubricantsas well as other pharmaceutical processing aids.

In the case of oral administration, fine powders or granules of thecompounds may be formulated with diluents, and dispersing and surfaceactive agents. They may also be prepared in water or in a syrup, incapsules or cachets, in the dry state or in a non-aqeous suspension,where a suspending agent may be included. The compounds may also beadministered in a tablet form along with optional binders andlubricants, or in a suspension in water or syrup, or an oil or in awater/oil emulsion and may include flavoring, preserving, suspending,thickening and emulsifying agents. The granules or tablets from oraladministration may be coated and other pharmaceutically acceptableagents and formulations may be utilized, which are well known to thoseof ordinary skill in the art.

The following examples are illustrative of preferred embodiments of theinvention and are not intended to be construed as limiting the inventionthereto. All percentages are based on weight of the final formulationunless otherwise indicated and the weight of all formulations totals100% by weight.

The novel compounds of the invention may readily be prepared by thefollowing synthetic routes: ##STR9##

PREPARATION OF EXAMPLE 1 7-Chloroquinoline-4-carboxaldehyde (7)

Selenium dioxide (4.52 g; 40.3 mmol) in a mixture of 25 ml of dioxaneand 6 ml of water was added in a dropwise fashion to 7-chlorolepidine(6; 6.50 g; 36.6 mmol) in 25 ml of dioxane to 65°-75° C. The temperaturewas raised to 85° C. and maintained there with stirring for 6 hours.After cooling, the-mixture was filtered through Celite™ andconcentrated. The crude material was purified on a flash column, elutingwith 10% ethyl acetate/hexane to obtain 5.24 g (74%) of aldehyde 7 as ayellow solid. ¹ H NMR (CDCl₃): δ 7.68 (d, 1H); 7.79 (d, 1H); 8.19 (d,1H); 9.01 (dd, 1H); 9.21 (m, 1H); 10.45 (s, 1H). IR (KBr): 1702, 1499,1216, 1041, 900, 653 cm⁻¹.

7-Chloro-4-[(diethoxyphosphinyl)ethenyl]quinoline (8)

To a stirred suspension of sodium hydride (978 mg of an 80% dispersion;32.6 mmol) in a 60 ml of THF at 0° C. was added 7.83 g (32.6 mmol) oftetraethylmethylenebisphosphonate in 20 ml of THF. After stirring atroom temperature (about 24° C.) for 1 hour, the solution was cooled to-78° C. and aldehyde 7 (5.20 g; 27.15 mmol) in 30 ml of THF was addeddropwise. The reaction was stirred at -78° C. for 30 minutes beforereturning to room temperature. After stirring for an additional 2 hours,the reaction was quenched with 10 ml of 10% NH₄ Cl. The product wasextracted into 2×10 ml of ethyl acetate; the organic layers werecombined, washed with 2×10 ml of brine and dried over MgSO₄. The solventwas evaporated and the crude product purified on a silica gel column,eluting with 2% methanol/ethyl acetate to obtain 7.6 g (86%) of theproduct as a syrup. ¹ H NMR (CDCl₃): δ 1.409 (t, 3H); 4.20 (q, 2H); 6.56(t, 1H, J=17 Hz); 7.58 (d, 1H, J=4.5 Hz); 7.57 (dd, 1H, J=2 Hz, 9 Hz);8.07-8.23 (m, H); 8.94 (d, 1H, J=4.5 Hz). IR (neat): 3492, 2983, 1604,1584, 1494, 1244, 1036, 964, 851, 787 cm⁻¹.

7-Chloro-4-[2'-(diethoxyphosphinyl)ethyl quinoline (9)

A mixture of vinyl phosphonate 8 (7.6 g; 23.35 mmol) and 5% palladium oncarbon (760 mg) in 50 ml of ethanol was hydrogenated at 50 psi ofhydrogen for 2 hours. The mixture was filtered through Celite™ andconcentrated. Thin layer chromatography indicated several productspresent. The crude residue was purified through a flash column (2%methanol/CH₂ Cl₂) to deliver 2.8 g (37%) of phosphonoethyl compound 9. ¹H NMR (CDCl₃): δ 1.34 (t, 3H); 2.14 (m, @H); 3.36 (m, 2H); 4.13 (q, 2H);7.27 (d, 1H, J=3.6 Hz); 7.55 (dd, 1H, J=2.2, 9 Hz); 7.98 (d, 1H, J=9Hz); 8.12 (d, 1H, J=2.2 Hz); 8.82 (d, 1H, J=3.6 Hz). IR (CDCl₃): 2985,1792, 1607, 1499, 1391, 1242, 907, 732 cm¹.

7-Chloro-4-[2'diethoxyphosphinyl)ethyl]quinoline-N-oxide (10)

A solution of 80% MCPBA (45 mg; 0.67 mmol) in 3 ml of CHCl₃ was added toquinoline 9 (200 mg; 0.61 mmol) in 2 ml of CHCl₃. After stirring at roomtemperature for 4 hours, an additional 53 mg of MCPBA was added andstirring was continued overnight. The reaction mixture was washed with2×1 ml of saturated Na₂ CO₃ and 2×1 ml of brine, dried (MgSO₄) and freedof solvent. The crude product was recrystallized from CH₂ Cl₂ /methyt-butyl ether to obtain 180 mg (86%) of the N-oxide as a crystallinewhite solid, mp 117° C. ¹ H NMR (CDCl₃): δ 1.34 (t, 3H); 2.13 (m, 2H);3.32 (m, 2H); 4.14 (q, 2H); 7.18 (d, 1H, J=6 Hz); 7.65 (dd, 1H, J=2, 9Hz); 7.98 (d, 1H, J=9 Hz); 8.47 (d, 1H, J=6 Hz) 8.85 (d, 1H, J=2 Hz). IR(KBr): 3091, 2980, 2908, 1566, 1430, 1240, 1024 cm⁻¹.

7-Chloro-4-[2'-(diethoxyphosphinyl)ethyl]quinolin-2-one

A solution on N-oxide 10 (400 mg; 1.16 mmol) and methanesulfonylchloride (266 mg; 2.32 mmol) in 4 ml of CH₂ Cl₂ was added to a two phasemixture of water (2 ml) and CH₂ Cl₂ (2 ml) containing 232 mg of NaOH and472 mg of tetrabutylammonium hydrogen sulfate. This mixture was stirredgently overnight. The layers were washed with brine, dried over MgSO₄,and concentrated. The residue was purl fled through a flash column,eluting with 5% methanol/CH₂ Cl₂, to obtain 260 mg (65% ) of 10 as ayellowish foam. ¹ H NMR (CDCl₃): δ 1.37 (t, 3H); 2.13 (m, 2H); 3.15 (m,2H); 4.18 (q, 2H); 6.62 (s, 1H); 7.22 (dd, 1H, J=1.5, 8.5 Hz); 7.50 (d,1H, J= 1.5 Hz); 7.66 (d, 1H, J=8.5 Hz). IR (CHCl₃): 3155, 1792, 1661,1471, 1381, 1095, 905, 733, 468 cm⁻¹.

7-Chloro-4-phosphonethylquinolin-2-one (1)

A solution of phosphonate 11 (250 mg; 0.73 mmol) in 6N HCl (9 ml) wasrefluxed overnight. The white precipitate which formed was collected andwashed with 3×2 ml cold H₂ O, 2×2 ml methanol, and 2×3 ml of ether, anddried in a vacuum desiccator. The product was obtained as a white solid,mp 303°-304° C. (180 mg; 86%). ¹ H (D20): δ 1.67-1.78 (m, 2H); 3.00-3.07(m, 2H); 6.55 (s, 1H); 7.18 (d, 1H); 7.42 (s, 1H); 7.85 (d, 1H). IR(KBr): 3062, 2944, 2895, 1675, 1560, 1507, 1458, 1352, 1187, 1070, 877,766 cm⁻¹. Anal. Calc'd. for C₁₁ H₁₁ NO₄ PCl: C, 45.91; H, 3.86: N, 4.87.Found: C, 45.77; H, 3.89; N, 4.82.

PREPARATION OF EXAMPLE 2 7-chloro-4-methylquinolin-2-one (13)

A solution of diketene (22.96 g; 0.33 mol) in 120 ml of toluene wasadded dropwise to a warmed (80° C.) solution of 3-chloraniline (33.82 g;0.27 mol) in 25 ml of toluene. The resulting mixture was heated toreflux for 5 hours. The orange crystalline material which formed wascollected and washed with cold hexane. After drying under vacuum, 40.60g (72%) of acetoacetanilide 12 was obtained, which was taken on directlyto the cyclization step. A solution of this product in concentrated H₂SO₄ (300 ml) was heated to 120° C. for 1 hour, then cooled and pouredinto ice-water. The yellowish precipitate was collected and washed withice-cold water and brine and dried under vacuum to obtain 33 g (90%) of13. ¹ H NMR (DMSO-d⁶): δ 2.33 (s, 3H); 6.50 (s, 1H); 7.30 (dd, 1H, J=2Hz, 8.6 Hz); 7.41 (d, 1H, J=2 Hz); 7.80 (d, 1H, J=86 Hz); 11.70 (br,1H). IR (KBr): 2797, 1691, 1401, 1383, 923 cm⁻¹.

2,7-Dichloro-4-methylquinoline (14)

A solution of quinolone 13 (10 g; 51.6 mmol) in 90 ml of POCl₃ wasrefluxed for 2 hours. After cooling, the mixture was poured into 300 gice-water and neutralized with NH₄ OH. The resultant precipitate wasfiltered off and washed with cold H₂ O. The crude product wasrecrystallized from 95% ethanol to obtain 8.95 g (72%) of 14. ¹ H NMR(CDCl₃): δ 2.71 (s, 3H); 7.28 (d, 1H); 7.55 (d, 1H); 7.92 (d, 1H); 8.08(d, 1H).

7 -Chloro-2 -methoxy-4-methylquinoline (15)

2-Chloroquinoline 14 (7.0 g; 32.8 mmol) was added to a solution ofsodium methoxide in methanol generated from 1.08 g (36.1 mmol) of 80%sodium hydride in 80 ml of methanol. The resulting mixture was refluxedovernight. It was filtered while still hot to remove undissolved matter.The product crystallized from the methanol upon cooling to deliver 6.1 g(70%) of 15 as a white solid. ¹ H NMR (CDCl₃): δ 2.62 (s, 3H); 4.10 (s,3H); 6.78 (s, 1H); 7.38 (d, 1H); 7.81 (d, 1H); 7.93 (d, 1H).

7-Chloro-4-bromomethyl-2-methoxyquinoline (16)

N-bromosuccinimide (6.40 g; 36 mmol) was added to a solution ofquinoline 15 (5.0 g; 24 mmol) in 50 ml of CCl₄. After irradiation with a60 W bulb for 1 hour, an additional 2 g of N-bromosuccinimide was addedand irradiation was continued for 30 minutes. After cooling, thesolution was filtered and the filtrate was concentrated under reducedpressure. An initial purification on a silica gel column, eluting with20% ethyl acetate in hexane, gave 720 mg of pure monobromide plus 5.5 gof a mixture containing monobromide 16 together with a minor amount ofdibromide. ¹ H NMR (CDCl₃): δ 4.05 (s, 3H); 4.71 (s, 2H); 6.94 (s, 1H);7.42 (dd, 1H, J=2, 9 Hz); 7.90 (m, 4H). IR (KBr): 2949, 2360, 1610,1407, 1468, 1345, 1198, 1028, 825, 694 cm⁻¹.

7 -Chloro-4-(diethoxyphosphinyl)methyl-2-methoxyquinoline (17)

A solution of bromide 16 (470 mg; 1.64 mmol) in triethylphosphite (4 ml)was refluxed overnight. The excess triethylphosphite was removed undervacuum and the residue was purified through a silica gel column elutingwith 3% methanol in CH₂ Cl₂ to obtain 300 mg (53%) of product as a whitecrystalline solid, mp 93.5°-94.5° C. ¹ H NMR (CDCl₃): δ 1.21 (t, 3H);3.50 (d, 2H, J=23 Hz); 4.04 (q, 2H); 6.88 (d, 1H, J=4 Hz); 7.36 (dd, 1H,J=2, 9 Hz); 7.88 (dd, 1H, J=2, 9 Hz). IR (KBr): 2978, 23589, 1607, 1383,1344, 1247, 1046, 1018, 964, 789 cm⁻¹.

7-Chloro-4-phosphonomethylquinolin-2-one (2)

A solution of diethylphosphonate 17 (160 mg; 0.57 mmol) intrimethylsilylbromide (4 ml) was refluxed overnight. The solvent/reagentwas removed in vacuo and the residue was dissolved in 3 ml of 1N NaOHand washed with 2×1 ml of ether. The aqueous layer was acidified to pH 1with 6N HCl and the precipitate which was formed was collected andwashed with cold water, methanol and ether. The product was obtained asa white solid, mp 186° C. (dec) (80 mg; 60%). ¹ H NMR (D20): δ 3.06 (d,2H, J=20.3 Hz); 6.54 (d, 1H, J=3.32 Hz); 7.12 (dd, 1H, J=2.03, 8.89 Hz);7.36 (d, 1H, J=2.03 Hz); 7.89 (d, 1H, j=8.80 Hz). IR (KBr): 2931, 2828,2360, 2309, 1658, 1643, 1532, 1406, 1224, 1147, 1093 cm⁻¹. Anal. Calc' dfor C₁₀ H₉ NO₄ ClP: C, 43.89; H, 3.32; N, 5.12. Found: C, 43.69; H,3.41; N, 5.02.

PREPARATION OF EXAMPLES 3 TO 5 3,5-Dichloracetoacetanilide (18a)

Diketene (39.7 g; 463 mmol) in 120 ml of toluene was added in a dropwisefashion to a solution of 3,5-dichloroaniline (62.2 g; 380 mmol) in 250of toluene at 80° C. After the addition was complete, the mixture wasrefluxed for 5 hours. The mixture was cooled and reduced to half itsvolume under reduced pressure, at which point the crude productprecipitated out of solution. The product was purified byrecrystallizing from ether/hexane to obtain 64.7 g (57%) of crystallinewhite solid, mp 69°-70° C. ¹ H NMR (CDCl₃): δ 2.05 (s, 3H); 3.60 (s,2H); 7.1-(s, 1H); 7.52 (s, 2H), 10.39 (br, 1H). IR (KBr): 3281, 3178,1712, 1648, 1589, 1543, 1445, 1414, 1360, 1196, 854, 802 cm⁻¹.

3-Iodacetoacetanilide (18b, mp 106°-107° C.) was prepared in the samemanner as (18a). ¹ H NMR (CDCl₃): δ 2.33 (s, 3H); 3.60 (s, 2H); 7.05 (t,1H, J=8 Hz); 7.45 (d, 1H, J=8 Hz); 7.51 (d, 1H, j+8 Hz); 7.97 (s, 1H) ,9.43 (br, 1H). IR (KBr): 3286, 1712, 1661, 1581, 1545, 1476, 1417, 1337,1162, 781, 766 cm⁻¹.

3,4 Dichloroacetanilide (18c, mp 88.5°-89.5° C.; 55%) was prepared inthe same manner as (18a). ¹ H NMR (CDCl₃): d 2.33 (s, 3H); 3.60 (s, 2H);7.36 (m, 2H); 7.80 (s, 1H); 9.38 (br, 1H). IR (KBr): 3289, 1720, 1666,1599, 1543, 1476, 1376, 1160, 1136, 879, 733 cm⁻¹.

3,5 Dicholoro-ω-bromoacetoacetanilide (19a)

A solution of bromine (3.27 g; 20.4 mmol) in 5 ml of CHCl₃ was added toa solution of the acetoacetanilide (5.0 g; 20.4 mmol) in 15 ml of CHCl₃in a dropwise fashion. The mixture was heated to 70° C. for 2 hours,then cooled and the precipitate collected and washed with methylenechloride and hexane. This crude product was purified through silica gelchromatography, eluting with 10% ethyl acetate/hexane, to obtain 1.35 g(20%) of a yellowish solid, mp 137° C. (dec). ¹ H NMR (CDCl₃); δ 3.85(s, 2H); 4.06 (s, 2H); 7.13 (s, 1H); 7.47 (m, 2H); 8.88 (br, (KBr):3283, 1731, 1663, 1586, 1540, 1417, 1327, 1049, 851, 669 cm⁻¹.

3-Iodo (19b, mp 102.5°-103.5° C.; 27%) was prepared in the same manneras (19a). ¹ H NMR (CDCl₃): δ 3.83 (s, 2H); 4.06 (s, 2H); 7.03 (m, 1H);7.46 (m, 2H); 7.92 (s, 1H); 8.67 (br, 1H). IR (KBr): 3250, 1738, 1651,1576, 1538, 1400, 1329, 1190, 1080, 784, 686 cm⁻¹.

3,4 Dichloro (19c, 40%) was prepared in the same manner as (19a). ¹ HNMR (CDCl₃): δ 3.84 (s, 2H); 4.12 (s, 2H); 7.37 (m, 2H); 7.78 (s, 1H);8.87 (br, 1H). IR (KBr): 3296, 1589, 1532, 1476, 1131, 1028, 812 cm⁻¹.

4-Bromomethyl-5,7-dichloroquinolin-2-one (20a)

A mixture of bromoacetoacetanilide 19a (1.33 g; 4.1 mmol) in 5 ml ofcon. H₂ SO₄ was heated to 120° for 1 hour, then cooled and poured into20 ml of ice water. The precipitate was collected and washed with coldwater and ether. After drying in a vacuum desiccator there was obtained800 mg (64%) of the product as a light brown solid, mp 259°-260° C.(dec). ¹ H NMR (DMSO-d⁶): δ 5.08 (s, 2H); 6.85 (s, 1H); 7.36 (s, 1H);7.43 (s, 1H); 12.16 (br, 1H). IR (KBr): 2834, 1668, 1599, 1399, 854, 730cm⁻¹.

4-Bromomethyl-7-iodoquinolin-2-one (20b, mp 298° C. [dec], 96%) wasprepared in the same manner as (20a). ¹ H NMR (DMSO-d⁶): δ 4.87 (s, 2H);6.76 (s, 1H); 7.59 (m, 2H); 7.70 (s, 1H); 11.83 (br, 1H). IR (KBr):2823, 1658, 1602, 1543 , 1412 , 887, 877 cm⁻¹.

4-Bromomethyl-6,7-dichloroquinolin-2-one (20a, mp 299°-301° C., 45%) wasprepared in the same manner as (20a). ¹ H NMR (DMSO-d⁶): δ 4.87 (s, 2H);6.76 (s, 1H); 7.46 (s, 1H); 8.03 (s, 1H). IR (KBr): 2867, 2800, 1666,1543, 1476, 1412, 1135, 895 cm⁻¹.

5,7-Dichloro-4-(diethoxyphosphinyl)methylquinolin-2-one (21a)

A mixture of bromomethylquinoline 20a (580 mg; 1.90 mmol) intriethylphosphite (6 ml) was refluxed overnight. The formed precipitatewas filtered and washed with ether. The crude material wasrecrystallized from acetone to deliver 540 mg of product (78%), mp210°-202° C. ¹ H NMR (DMSO-d⁶): δ 1.11 (t, 6H); 3.32 (s, 1H); 3.97 (m,5H); 6.53 (d, 1H, J=4 Hz); 7.33 (d, 1H, J=2 Hz); 7.36 (d, H, J=2 Hz);12.05 (br, 1H). IR (KBr): 2985, 1682, 1589, 1234, 1059, 1034, 1023, 964cm⁻¹.

7-Iodo-4-(diethoxyphosphinyl)methylquinolin-2-one (21b, mp 196.5°-197.5°C., 55%) was prepared in the same manner as (21a). ¹ H NMR (DMSO-d⁶): δ1.03 (t, 3H); 3.57 (d, 2H, J= 22 Hz); 4.01 (q, 4H); 6.55 (d, 1H); 7.46(d, 1H); 7.61 (d, 1H); 7.69 (s, 1H); 11.75 (br, 1H). IR (KBr): 2980,1661, 1260, 1028, 872 cm⁻¹.

4- (Diethoxyphosphinyl)methyl-6,7-dichloroquinolin-2-one (21c, mp219°-222° C.; 38%) was prepared in the same manner as (21a). ¹ H NMR(CDCl₃): δ 1.25 (t, 6H); 3.37 (d, 2H, J=23 H₂); 4.12 (q, 4H); 6.72 (d,1H); 7.56 (s, 1H); 7.91 (s, 1H). IR (Kbr): 2980, 1664, 1476, 1409, 1247,1031 cm⁻¹.

5,7-Dichloro-4-phosphonomethylquinolin-2-one

A solution of the phosphonate (200 mg; 0.55 mmol) in 6N HCl (5 ml) wasrefluxed overnight. The solvent was removed under reduced pressure andthe residue was dissolved in 3 ml 1N NaOH and washed with 3×1 ml ether.The aqueous layer was acidified with 3N HCl, with cooling, and theresultant precipitate was collected, washed with cold water, methanol,and ether, and dried (NMR (D₂ O): δ 3.59 (d, 2H, J=20.6 Hz); 6.55 (d,1H, J=4.5 Hz); 7.12 (d, 1H, J=2 Hz); 7.25 (d, 1H, J=2 Hz). IR (KBr):2926, 2317, 1656, 1594, 1520, 1450, 1394, 1198, 1003, 938, 728 cm⁻¹.Anal. Calc'd for C₁₀ H₈ NO₄ Cl₂ P: C, 38.99; H, 2.62; N, 4.55. Found: C,38.90; H, 2.66; N, 4.53.

7-Iodo-4-phosphonomethylquinolin-2-one (4, mp 239°-331° C.; 60%) wasprepared in the same manner as (3). ¹ H NMR (D₂ O): δ 2.97 (d, 2H,J=20.2 Hz); 6.49 (d, 1H, J=3 Hz); 7.34 (d, 1H, J=8.7 Hz); 7.54 (d, 1H,J=8.7 Hz); 7.69 (s, 1H). IR (KBr): 2924, 2327, 1643, 1525, 1448, 1365,1270, 1178, 1005 cm⁻¹. Anal. Calc'd For C₁₀ H₉ NO₄ IP: C, 32.90; H,2.48; N, 3.84. Found: C, 32.84; H, 2.52; N, 3.80.

6,7-Dichloro-4-phosphonomethylquinolin-2-one (5, mp 213 °-218° C. [dec];68%) was prepared in the same manner as (3). ¹ H NMR (D₂ O): δ 2.80 (d,2H, J=20.1 Hz); 6.37 (s, 1H); 7.26 (s, 11H); 7.71 (s, 1H). IR (KBr):2900, 1646, 1406, 1234, 1005, 879 cm⁻¹. Anal. Calc'd for C₁₀ H₈ NO₄ Cl₂P--0.05 H₂ O: C, 37.88; H, 2.86; N, 4.42. Found: C, 37.98; H, 2.85; N,4.41.

Inhibition of EAA-Induced Currents in Xenopus oocytes

Defolliculated oocytes obtained from Xenopus laevis females wereinjected with 30-75 ng of poly (A+) mRNA obtained from 21-day old maleSprague-Dawley rats. Oocytes were placed individually in 100 ml ofantibiotic-supplemented modified Barthes solution (MBS, containing inmM: NaCl, 88; KCl, 1.0; NaHCO₃, 2.4 HEPES, 10; MgSO₄ 0.82; Ca(NO₃)₂,0.33) in 96-well sterile plates and cultured for 48-120 hours prior toexperimentation. Oocytes were inspected every 24 hours at which time thebathing solution is replaced with fresh MBS.

For electrophysiological studies, oocytes were positioned in a smallrecording chamber (500 ml) and superfused with antibiotic free MBSsupplemented with CaCl₂ (final concentration=1.4 mM). Oocytes areimpaled with a single glass microelectrode, voltage clamped at -60 to-70 mV, and perfused by gravity feed at a rate of 3-5 ml/min at roomtemperature. Drugs are dissolved in the perfusate (pH adjusted to7.3-7.4) and perfused for 1-2 min or until the response has reached aplateau, followed by a 4 min perfusion in the absence of drug(s).Antagonists are coperfused with agonists. MBS used in NMDA assays isprepared from "glycine-free", deionized water.

Potencies to inhibit kainic acid-, AMPA- and NMDA/glycine-inducedcurrents are determined from concentration-response curves. IC₅₀ valuesare converted to K_(i) values for comparison purposes using theCheng-Prusoff equation. In Table I, only KA induced currents were lookedat; no AMPA responses were evaluated for these compounds. The dataindicate the ability of these compounds to block KA induced functionalresponses. The data in Table II indicate that the compounds 1-5 havesignificant affinity for CNQX-labeled non-NMDA receptors and that thisaffinity parallels their ability to block KA induced responses. Thecompounds vary in their selectivity for NMDA vs non-NMDA receptors;Compounds 1, 3, and 5 are quite selective, while compounds 2 and 4 arenot very selective.

Several other related compounds were tested but found to be essentiallyinactive. These compounds include5,7-Dichloro-4-(diethoxyphosphinyl)methylquinolin-2-one (21a),2-Carboxy-7-chloro-4-phosphonethylquinoline (22), ##STR10##2-Carboxy-7-chloro-4-phosphonomethylquinoline (23), ##STR11##7-Chloro-4-phosphonoquinolin-2-one (24) ##STR12##7-Chloro-8-nitro-4-phosphonomethylquinolin-2-one (25), ##STR13## and6-Chloro-5-nitro-4-phosphonomethylquinolin-2-one (26). ##STR14##

Inhibition of EAA Receptor Ligand Binding

Binding assays for the displacement of [³ H]AMPA were performed asdescribed by Murphy et al. (Neurochemical Research. 12: 775-781 [1987]).KA binding assays were performed as described by London et al (MolecularPharmacology. 15: 492-505 [1979]); strychnine insensitive glycinebinding was evaluated by the method of Snell et al (European Journal ofPharmacology. 156: 105-110 [1988].

The results are set forth in Tables I and II.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of theclaims.

                  TABLE I                                                         ______________________________________                                        Potencies of example compounds to inhibit KA-induced                          currents in rat brain mRNA-injected Xenopus oocytes:                          Example      K.sub.i (μM)                                                  ______________________________________                                         1           51                                                                2           32                                                                3           18.2                                                              4           15.6                                                              5           9.6                                                               21a         480                                                              22           450                                                              23           129                                                              24           >>100                                                            25           379                                                              36           >300                                                             ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Inhibition of EAA Receptor Ligand Binding                                     Receptor Potency (K.sub.i, μM)                                             Example  GLU          CNOX      Glycine                                       ______________________________________                                         1        600         91        231                                            2         30         59        10                                             3       >100         38        28                                             4         35         26        29                                             5       >100         15        79                                             21a                  >100      103                                           22       >100         384       >1000                                         23                    64        68                                            24       >300         nd        >1000                                         25       >1000        300       >1000                                         26       >1000        >1000     >1000                                         ______________________________________                                    

What is claimed is:
 1. A compound having the formula: ##STR15## whereinn is 0, 1, 2, or 3; R1 and R2 are independently selected from the groupconsisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy,hydroxyl, hydroxymethyl, C₁ to C₆ lower alkyl and C₇ to C₁₂ higheralkyl, aryl and aralkyl; and the pharmaceutically acceptable saltsthereof.
 2. The compound according to claim 1 wherein n is
 1. 3. Thecompound according to claim 1 wherein n is
 2. 4. The compound accordingto claim 1 and being 7-chloro-4-phosphonoethylquinolin-2-one.
 5. Thecompound according to claim 1 and being7-chloro-4-phosphonomethylquinolin-2-one.
 6. The compound according toclaim 1 and being 7-iodo-4-phosphonomethylquinolin-2-one.
 7. Thecompound according to claim 1 and being5,7-dichloro-4-phosphonomethylquinolin-2-one.
 8. The compound accordingto claim 1 and being 6,7-dichloro-4-phosphonomethylquinolin-2-one. 9.The compound according to claim 1 wherein R1 and R2 are not bothhydrogen.
 10. A pharmaceutical composition for relieving pain, treatmentof convulsions or epilepsy, treating cerebral ischemic damage, andtreating emesis which comprises: an effective amount of a compoundaccording to claim 1 together with a pharmaceutically acceptablecarrier.
 11. A method for antagonizing excitatory amino acid kainic acidand/or AMPA receptors by utilizing a compound having the generalformula: ##STR16## wherein n is 0, 1, 2, or 3; R1 and R₂ areindependently selected from the group consisting of hydrogen, halogen,halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C₁ to C₆lower alkyl and C₇ to C₁₂ higher alkyl, aryl and aralkyl; and thepharmaceutically acceptable salts thereof.